Edoxaban versus Warfarin in Patients

withAtrial Fibrillation

Robert P.Giugliano et alNew Engl JMed Nov 19,2013

Effective ANticoaGulation with

Factor XA next GEneration in

Atrial Fibrillation – Thrombolysis In

Myocardial Infarction 48 (ENGAGE AF TIMI 48)

Introduction

• Atrial Fibrillation (AF) is the most common type of arrhythmia.

• It is a supraventricular arrhythmia characterized

electrocardiographically by low amplitude baseline oscillations

(fibrillatory or f waves) and an irregularly irregular ventricular

rhythm.

• Thromboembolic complications are common with AF.

• Warfarin has been the sole effective agent in preventing

thromboembolic complications in pts with AF,but with risk of

hemorrhage.

• Newer agents came into usage and are in pipeline ,as efficacious

as warfarin but with decreased risk of hemorrhage.

Background

• Edoxaban is a oral, reversible,direct factor Xa inhibitor, having

linear and predictable pharmacokinetic profile.

• 62% bioavailability, with proven antithrombotic effects.

• Max. conc. within 1-2 hours and 50% is excreted by the kidney.

• The long term efficacy and safety of edoxaban as compared

with warfarin in patients with AF is not known.

Two dose regimens of once daily edoxaban with

warfarin in patients with AF who were at

moderate to high risk for stroke.

Trial design

• It is a three group, randomized, double blind, double

dummy trial comparing two dose regimens of edoxaban

with warfarin.

• 1393 centers in 46 countries.

• November 19, 2008 through November, 2010.

Inclusion criteria

Randomized and study drugs

• Patients were randomly assigned in a 1:1:1 ratio, to receive warfarin,

dose adjusted to achieve an INR of 2.0 to 3.0,or to receive high

dose(60mg) or low dose edoxaban(30mg).

• Randomization of patients who were already on vitamin K antagonist

was done after their INR was 2.5 or less.

• Randomization was stratified according to

CHADS2 score of 2 or 3 vs 4,5,6

Status with respect to the need for reduction in the edoxaban dose.

Dose of edoxaban was halved in case …

• At the time of randomization or during the study if…

Estimated CrCl <30 to 50 ml/min.

A body weight of <60kg

Concomitant use of P-glycoprotein inhibitors

(verapamil or quinidine,dronedarone).

P Glycoprotein inhibitors• Permeability glycoprotein, abbreviated as P-gp or Pgp • Also known as multidrug resistance protein 1 (MDR1) or ATP-

binding cassette sub-family B member 1 (ABCB1) or cluster of differentiation 243 (CD243)

• Encoded by the ABCB1 gene.• Expressed in the intestinal epithelium, hepatocytes, renal PCT cells,

adrenal gland and capillary endothelial cells comprising the BBB.

• It is inhibited by many drugs, such as: Amiodarone,Azithromycin Captopril,Clarithromycin,Cyclosporine Quinidine,Quinine, Reserpine,Ritonavir Verapamil

Study end points

The primary efficacy end point

• Time to the first adjudicated stroke (ischemic or hemorrhagic)

• Systemic embolic event (SEE).

The principal safety end point was

• Adjudicated major bleeding during treatment ,as defined by the

International Society on Thrombosis and Haemostasis.

Secondary composite end points

• Stroke,SEE,death from CV causes,MI.

Net clinical end points

• included the above all.

Results

• Total of 21,105 pts underwent randomization.

• 21,026(99.6%) received the study drug.

• A total of 5330(25.3%) received a reduced dose of edoxaban or

matching placebo at randomization.

• After randomization , dose reductions occurred in 7.1% pts,and dose

increases in 1.2% with similar rates in three treatment groups.

• Median duration of treatment exposure was 907 days, excluding

interruptions.

• Median follow up was 1022 days.

Primary end point

EVENTS WARFARIN GROUP

HIGH DOSE EDOXABAN

P VALUE LOW DOSE EDOXABAN

P VALUE

STROKE or SYSTEMIC EMBOLISM

232 (1.50%/yr) 182 (1.18%/yr) P<0.001P=0.02

253 (1.61%/yr)

P=0.005P=0.44

ANNUALIZED RATE (ITT)

1.80%/yr 1.57%/yr 2.04%/yr

HEMORRHAGIC STROKE

0.47% 0.26% P<0.001 0.16% <0.001

ISCHEMIC STROKE

1.25% 1.25% 1.77%

MAJOR BLEEDING EVENTS

3.43% 2.75% 1.61%

LIFE THREATENING BLEEDING

0.78% 0.40% 0.25%

Bleeding

OUTCOME WARFARIN(%of pts/yr)

HIGH DOSE EDOXABAN

LOW DOSE EDOXABAN

P VALUE

MAJOR BLEEDING 524 (3.43%) 418 (2.75%) 254 (1.61%) <0.001

FATAL 59 (0.38%) 32 (0.21%) 21 (0.13%) <0.001

IC BLEED 132 (0.85%) 61 (0.39%) 41(0.26%) <0.001

FATAL IC BLEED 42(0.27%) 24 (0.15%) 12 (0.08%) <0.001

GI BLEED 190 (1.23%) 232 (1.51%) 129 (0.82%) <0.001

LIFE THREATENING BLEED

122 (0.78%) 62 (0.40%) 40 (0.25%) <0.001

MINOR BLEEDING 714 (4.89%) 604 (4.12%) 533 (3.52%) <0.001

GI bleed more in high dose edoxaban

Secondary and other efficacy outcomes

• Rates of all three prespecified secondary composite

outcomes were significantly lower with high dose

edoxaban

• Lower annualized rates of CV death with edoxaban

(2.74% vs 3.17%).

HIGH DOSE EDOXABAN < WARFARIN

LOW DOSE EDOXABAN =WARFARIN

Discussion

• Both doses of edoxaban were non inferior to warfarin.• High dose edoxaban more effective than warfarin.• Rate of ischemic strokes high dose edoxaban = warfarin <

low dose edoxaban.• Rate of hemorrhagic strokes,CV deaths less in edoxaban

groups.• All bleedings except GI bleed were low in edoxaban

group.

Comparison of edoxaban regimensRate of stroke,systemic

embolic event

Reduction in incidence of ischemic strokes (29%)

Hemorrhagic strokes (49 vs 33

events)

No significant differences between the two edoxaban groups in the rates of death from cardiovascular causes and death from any cause

HIGH DOSE EDOXABAN vs LOWDOSE EDOXABAN

Anticoagulants

Warfarin50yrs

Rodent poison

Dabigatran

Factor IIa inhibitor

RivaroxabanFactor Xa inhibitor

ApixabanFactor

xa inhibitor

Edoxaban

Factor Xa

inhibitor

Warfarin• Water soluble VKA,initially developed as rodenticide.• Inhibits synthesis of vitamin K dependent clotting factors –

II,VII,IX,X and anticoagulants proteins C and S.• Inhibits VKOR,thereby blocking carboxylation.• Antithrombotic effect of warfarin depends on a reduction in

the functional levels of factor X(t1/2 24hrs),prothrombin(t1/2 72hrs)

• Racemic mixture• Completely absorbed.• 97%bound to albumin.• Coagulation monitoring is essential,narrow Therapuetic

index.

Metabolism of warfarin

Warfarin

S isomerMore active

CYP2C9*2

Homozygosity 50-70% reduction

Heterozygosity25-30%

reduction

CYP2C9*3 VKORC1

A/Aheterozygotes -

25%

A/A homozygotes

50%

R isomer

CYP1A1CYP1A2CYP3A4

Warfarin name ….?

Wisconsin Alumni Research Foundation

+ the ending -arin indicating its link with coumarin. Dosing regimen Tait,Kovacs,Fennerty

• Flat nasal bridge ,• laryngomalacia,• pectus carinatum,• ventriculomegaly,• Agenesis ofcorpus

callosum,• stippled epihpysis

Trials of New anticoagulants

Clinical condition

Dabigatran Rivaroxaban Apixaban

Post op VTEProphylaxis(TKA)

RE-MODELRE MOBILIZE

RECORD 3,4 ADVANCE 1,2

Result Dabigatran>enoxaparin(36.4 vs 37.7%)

Rivaroxaban>enoxaparin(9.6 vs18.9%)

Apixaban>enoxaparin(15 vs24%)

Post opVTE prophylaxia (THA)

RE-NOVATE RECORD 1,2 ADVANCE 3

Result 6.0% vs 6.7% 1.1% vs 3.7% 1.4% vs 3.9%

AF RELY ROCKET AF AVEREOS(failed warfarin

ARISTOTLE(warfarin)

Acute VTE RECOVER EINSTEIN AMPLIFY EXT

Result 2.4% vs 2.1% 2.1 vs 3.0% 1.7% vs 8.8%

Medically ill MAGELLAN

Result Rivaroxaban >enoxa

Trials on edoxaban• 1.A randomized,dose ranging,warfarin controlled,phase 2 study

involving 1146 pts with AF showed that once daily doses of Edoxaban(60 mg or 30mg) were safer than twice daily doses.

Thromb Haemostat 2010;104:633-41

• 2.A phase 3 study involving 8292 patients with Acute Venous Thromboembolism showed that once daily Edoxaban at a dose of 60 mg (reduced to 30 mg in selected patients) was as effective as Warfarin for the prevention of recurrent symptomatic venous thromboembolism and associated with significant lower rate of bleeding.

NEJM2013;369:1406-15

AnticoagulantsDRUG TRADE

NAMETRIALS FDA

Approvalyear

Year of entry into market

Indications

WARFARIN COUMADIN YES 48$/yr AF,VTE,Prosthetic heart valves

NICOUMALONE ACITROM YES 41.50$/60 tabs

DABIGATRAN PRADAXA RELY YES(Oct,2010)

3000$/yr

VTE,AF

RIVAROXABAN XARELTO(BAYER)

ROCKET AF YES(Nov,2011)

725Rs/Tablet

VTE,AF

APIXABAN ELIQUIS ARISTOTLE YES(Dec,2012)

VTE,AF

EDOXABAN LIXIANA ENGAGE AF TIMI 48

NO (?2014)

Summary of new oral anticoagulants

• Broad therapeutic window• No need of frequent monitoring.• Dose to be adjusted in renal failure.• Caution with the use of Glycoprtoein P inhibitors.• Not to be used with glycoprotein Pinducers(rifamipicin)• Dabigatran causes acidity.• Apixaban in case of recent GI bleeding.• Not indicated in valvular AF.• Dabigatran,apixaban in pts with ischemic stroke on

warfarin.

Dr.PraveenNagula